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Background: D-dimer, generated upon the degradation of fibrin, is extensively used to detect thrombosis in various diseases. It is also explored as a marker for thrombosis in cases with COVID-19 disease. Few studies have confirmed its utility as a marker for assessing disease severity. Objectives: The current research was undertaken to determine the role of D-dimer in patients with COVID-19 and to investigate any association with the progression and severity of the disease in the Saudi population. Methods: Clinical indices in confirmed COVID-19 patients were collected from tertiary care hospitals in Aljouf and Qassim regions. The plasma D-dimer levels were quantified directly in the samples collected from COVID-19 patients (<i>n</i> = 148) using an immunofluorescence assay, and the data were presented in Fibrinogen Equivalent Units (mg/L). The collected data of D-dimer were analyzed based on COVID-19 severity, age, and the gender of patients. Results: The findings show that the plasma D-dimer concentrations were significantly (<i>p</i> = 0.0027) elevated in COVID-19 cases (<i>n</i> = 148), compared to in the normal healthy uninfected controls (<i>n</i> = 309). Moreover, the D-dimer levels were analyzed according to the severity of the disease in the patients. The data revealed that D-dimer concentrations were significantly increased in patients with mild infection to moderate disease, and the levels were the highest in patients with severe COVID-19 disease (<i>p</i> < 0.05). Our analysis demonstrates that the D-dimer levels have no association with the age or gender of COVID-19 patients (<i>p</i> > 0.05) in the study population. Conclusions: D-dimer can serve as a biomarker not only for the detection of COVID-19 infection, but also for determining the severity of infection of COVID-19 disease.